Diverse Molecular Characteristics And Clinical Outcomes Of Commonly Used Treatments In RET-rearranged Advanced Non-small-cell Lung Cancer

BackgroundThe widely acceptance among clinicians of testing for less common genomic alterations—like RET,has raised concerns over the treatments of patients whose tumors harbor it.In RET-rearranged advanced non-small-cell lung cancers(NSCLC),though it has been proved as tumorigenic and targetable,molecular features and clinical outcomes of the mainstay therapeutics were not well illustrated.In this study,we presented molecular features and clinical outcomes of these patients treated with chemotherapy,immune checkpoint inhibitors(ICIs)and multi-kinase inhibitors(MKIs).Besides,resistance mechanisms to osimertinib have raised growing concerns,but those with acquired RET rearrangement is poorly characterized.MethodsPatient information was collected retrospectively from the Guangdong Lung Cancer Institute.From January 1st,2013 to February 28th,2019,all patients with advanced NSCLC carrying RET rearrangement,were identified.Their clinicopathologic,genetic,immune characteristics and response to therapy were obtained.Two independent pathologists verified all the histological diagnosis.RET rearrangement was determined by commercial next generation sequencing(NGS)assays or any of FISH,RT-PCR.For NGS,DNA was extracted from tissues,either formalin-fixed,paraffin-embedded tumor tissues or freshly frozen tissues storage at-80 ℃,or liquid samples including plasma,cerebrospinal fluid and pleural effusion.NGS data was used to describe an integrated picture of genetic profile,and to determine microsatellite instability(MSI)status.Tumour mutation burden(TMB)was calculated by counting the number of somatic,coding,insertions,deletion mutations and single nucleotide variants per megabase(Mb)of genome examined by NGS.PD-L1 by immunohistochemistry(IHC).In clinical analysis for NSCLC patients with RET rearrangement acquired after resistance to EGFR TKIs,we retrospectively identified advanced,EGFR-mutant NSCLC patients treated with osimertinib between April 9th,2015 and November 1st,2018 at our institute.Clinicopathologic features and clinical outcomes were analyzed.Subsequent genetic profiling was performed at the time of progression by next-generation sequencing(NGS).Overall survival(OS)since 1st line treatment was calculated from first-line treatment start to death or last follow up,and OS post-progression was calculated from osimertinib progression.Median follow-up time was 43.4 months.ResultsA total of 39 RET-rearranged patients were enrolled from January 2013 to February 2019.Most of them(37/39,95%)had co-occurred genetic alterations by next generation sequencing.Concomitant TP53 mutation appeared most frequently(53%).Two patients harboured additional EGFR sensitive mutations at the time of diagnosis,concomitant EGFR-sensitising were as follows:exon19 deletion and exon21 L858R,One patient harboured concomitant EGFR amplification.No other concurrent oncogenic driver mutation was found.TMB ranged from 1 muts/Mb to 15.9 muts/Mb.All the cases assessed were MS-Stable.High(≥50%),intermediate(1-49%),and negative(<1%)PD-L1 expression was observed in 8/24(33%),10/24(42%)and 6/24(25%)cases,respectively.We found no significant difference between tumours with different RET fusion partners(KIF5B and non-KIF5B)in terms of TMB,MSI and PD-L1 status.Progression-free survival(PFS)was not significantly different across three treatments(P=0.056).Among 10 patients treated with ICIs,disease control rate was 60%and objective response rate was 10%.Three patients had durable PFS from 6.3 to 11.5 months,including one heavily-pretreated patient with high level of PD-L1 expression.In the 192 patients treated with osimertinib,57 had follow-up NGS information after progression,and six harboured acquired RET rearrangement(11%,6/57).For patients with RET rearrangements when progressed on osimertinib,OS since 1st line treatment(22.9m vs 59.5m,P=0.021)and OS post-progression(2.1m vs 10.0m,P=0.031)were significantly shorter compared with non-RET-rearranged cases,whereas no significant difference was found in demographics at the initial lung cancer diagnosis or progression-free survival(PFS)of osimertinib(12.1m vs 5.8m,P=0.34).Among these six patients,one received best supportive care,two continued to use drugs targeting EGFR but deteriorating soon,three patients tried osimertinib combined with cabozantinib with one benefit from this combination approach.ConclusionsRET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations,TMB,and PD-L1 expression.Concurrent genetic alterations were not excluding factor for patients receiving ICI treatment.A subgroup of RET-rearranged patients could benefit from ICIs,which warrants further exploration and precise diagnosis.RET rearrangements could exist in EGFR-mutant NSCLC with acquired resistance to osimertinib and linked to inferior survival.Study on the molecular evolution and heterogeneity during treatment course are warranted for further therapeutic strategies.